1. Field of the Invention:
The present invention relates to novel thiopyran derivatives. More specifically, this invention is concerned with benzothiopyran derivatives, thienothiopyran derivatives and salts thereof, said derivatives and salts being useful for the prevention or treatment of ischemic heart diseases such as angina pectoris, arrhythmia, myocardial infarction, congestive heart failure and post PTCA restenosis, cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after subarachnoid hemorrhage, peripheral circulatory disturbance such as arteriosclerosis obliterans, thromboangina oblite, Raynaud disease, Buerger disease, and/or hypertension; their preparation processes; and pharmaceuticals comprising them as effective ingredients.
2. Discussion of the Background
Serotonin is a compound contained abundantly in platelets, which are a blood component, and in a central nervous system, it acts as a neurotransmitter. In platelets, it is released upon stimulation by thromboxane A.sub.2, ADP, collagen or the like and synergistically acts on various platelet aggregation factors or vasoconstrictors through activation of serotonin-2 receptors in the platelets and vascular smooth muscle cells, thereby inducing strong platelet aggregation and vasoconstriction [P. M. Vanhoutte, "Journal of Cardiovascular Pharmacology", Vol. 17 (Supple. 5), S6-S12 (1991)].
Serotonin is also known to potentiate proliferation of vascular smooth muscle cells [S. Araki et al., "Atherosclerosis", Vol. 83, p29-p34(1990)]. It has been considered that, particularly when endothelial cells are injured as in arteriosclerosis or myocardial infarction, the vasoconstricting action and thrombus forming action of serotonin are exasperated, thereby reducing or even stopping blood supply to myocardial, cerebral and peripheral organs [P. Golino et al., "The New England Journal of Medicine", Vol. 324, No. 10, p641-p648 (1991), Y. Takiguchi et al., "Thrombosis and Haemostasis", Vol. 68(4), p460-p463 (1992), A. S. Weyrich et al., "American Journal of Physiology", Vol. 263, H349-H358 (1992)].
Being attracted by such actions of serotonin or serotonin-2 receptors, various attempts are now under way to use a serotonin-2 receptor antagonist as a pharmaceutical for ischemic diseases of the heart, the brain and peripheral tissues.
Several compounds such as sarpogrerate are known to possess the serotonin-2-receptor antagonistic action. These compounds still exhibit many problems to be solved, such as the intensity of the activity, toxicity, and side effects. A drug exhibiting both the anti-serotonin action and the .alpha..sub.1 blocking action has a possibility of alleviating side effects such as orthostatic hypotension and reflex pulsus frequens which involve antihypertensive action due to the .alpha..sub.1 blocking action. In addition, because hypertension is a major risk factor in ischemic heart diseases, the drug exhibiting both the anti-serotonin action and the .alpha..sub.1 blocking action has the potential of being extremely effective for the treatment and prevention of hypertension and ischemic heart diseases.
In view of this situation, the inventors of the present invention have undertaken extensive studies and discovered thiopyran derivatives exhibiting a strong serotonin-2-recepter antagonistic action and useful as a drug for preventing or treating ischemic heart diseases, cerebrovascular disturbance, and peripheral circulatory disturbance, with minimal toxic or side effects. In addition, some of the compounds among the thiopyran derivatives were found to also possess the .alpha..sub.1 blocking action and are thus useful as antihypertensive agents with less side effects, and can therefore be widely used in the treatment and prevention of circulatory diseases.